Although B cells from immature mice and from adult X-chromosome linked immunodeficient mice do not exhibit a proliferative response to anti-immunoglobulins, a brief pronase treatment of cells induced responsiveness in these populations as well as markedly enhanced the responsiveness of normal adult populations. Similarly, trypsin, papain and subtilisin treatment of normal cells yielded enhanced responsiveness to anti-immunoglobulin. These results have been interpreted to suggest that protease sensitive sites on the surface of B cells function to regulate the proliferative response possibily as a means of precluding premature proliferation of cells which may be immature as regards their overall immune response capability. Antibodies with specificity for the F(ab prime)2 moiety of surface immunoglobulins were incapable eliciting a proliferative response in normal adult murine splenocytes whereas antibodies specific for the mu-chain of presumably the same surface cells respond readily to anti-F(ab prime)2 antibody. By contrast, responsiveness to anti-F(ab prime)2 essentially was not observed upon treatment of cells with trypsin, papain or subtilisin in place of Pronase suggesting that the protease sensitive site involved in regulating response to anti-mu is not identical to the Pronase sensitive site involved in responsiveness to anti-F(ab prime)2. It should be emphasized that the F(ab prime)2 moiety of surface immunoglobulin bears the antigen combining domain and for this reason the nature of the site controlling responsiveness to anti-F(ab prime)2 may have special relevance. Cytosol fractions from murine lymphocytes cultured with but not without Sepharose-linked anti-immunoglobulin markedly stimulated the DNA synthesis of Xenopus laevis splenic nuclei. Employing this assay, the time of appearance of the active component in the cell sap of cultured cells coincided well with the time of onset of DNA synthesis by intact cells cultured with Sepharose-anti-immunoglobulin as would be expected for a relatively late signal if not the ultimate signal involved in induction of DNA synthesis.